Synthesis of acylhydrazones of sterically hindered hydroxybenzaldehydes based on phloroglucinol

Article abstract of DOI:10.1134/S1070428014060086

New acylhydrazones containing sterically hindered phenolic fragments with different degrees of steric shielding were synthesized by reactions of 2,2,2-[benzene-1,3,5-triyltris(oxy)]triacetic acid trishydrazide with hydroxybenzaldehydes. According to the N

Full text of DOI:10.1134/S1070428014060086

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 6, pp. 805–809. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © T.A. Barsukova, G.N. Nugumanova, S.V. Bukharov, S.N. Podyachev, V.V. Syakaev, N.A. Mukmeneva, R.Ya. Deberdeev, 2014,
published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 6, pp. 823–827.
Dedicated to Full Member of the Russian Academy of Sciences
O.N. Chupakhin on his 80th anniversary
Synthesis of Acylhydrazones of Sterically Hindered
Hydroxybenzaldehydes Based on Phloroglucinol
T. A. Barsukovaa, G. N. Nugumanovab, S. V. Bukharovb, S. N. Podyacheva, V. V. Syakaeva,
N. A. Mukmenevab, and R. Ya. Deberdeevb
a Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences,
ul. Arbuzova 8, Kazan, 420088 Tatarstan, Russia
b Kazan National Research Technological University, ul. K. Marksa 68, Kazan, 420015 Tatarstan, Russia
e-mail: gulia_nn@yahoo.com
Received April 11, 2014
Abstract—New acylhydrazones containing sterically hindered phenolic fragments with different degrees of
steric shielding were synthesized by reactions of 2,2′,2″-[benzene-1,3,5-triyltris(oxy)]triacetic acid trishydra-
zide with hydroxybenzaldehydes. According to the NMR data, the products in solution exist as relatively stable
conformational cis/trans isomers with respect to the C(O)–NH bond.
DOI: 10.1134/S1070428014060086
Symmetric sterically hindered benzenetriol deriva-
tives attract strong interest from the practical view-
point as efficient, heat-resistant, and nontoxic antioxi-
dants [1]. High antioxidant activity of such compounds
as 1,3,5-tris(3,5-di-tert-butyl-4-hydroxybenzyl)mesity-
lene and 1,3,5-tris(3,5-di-tert-butyl-4-hydroxybenzyl)-
resorcinol is determined, among other factors, by their
steric structure [2]. Molecules of these compounds
adopt a basket conformation which favors cooperative
effect of phenolic hydroxy groups [3, 4].
A promising class of polyfunctional antioxidants
comprises hybrid structures based on sterically
hindered phenols and hydrazones. The latter exhibit
thermal and light stabilizer properties and are capable
of acting as traps for peroxy radicals, forming com-
plexes with transition metals, and promoting hydro-
peroxide degradation according to the molecular
mechanism [5, 6].
The goal of the present work was to synthesize new
efficient polyfunctional antioxidants for polymers and
organic media. For this purpose, we examined reac-
tions of phloroglucinol derivatives with sterically
hindered hydroxybenzaldehydes characterized by dif-
ferent degrees of steric shielding. New symmetric acyl-
hydrazones IVa and IVb were obtained according to
Scheme 1.
It is known that under normal conditions acylhydra-
zones can exist as different conformers resulting from
cis/trans isomerism with respect to the amide bond and
E/Z isomerism with respect to the double C=N bond
[7]. Moreover, molecules IVa and IVb contain a num-
ber of polar groups which may be involved in hydro-
1
gen bonds. Therefore, the H NMR spectra of these
compounds recorded at room temperature display
fairly complicated patterns, and each group of protons
gives rise to a number of signals. Elevated temperature
facilitates conformational transitions and hydrogen
bond rupture, which leads to simpler spectra.
1
The H NMR spectra of IVa and IVb in DMSO-d6
at 130°C contained distinct singlets from protons in
the tert-butyl groups (δ 1.30–1.44 ppm), a broadened
singlet from the methylene protons (δ 4.75–4.80 ppm),
singlets from aromatic protons (δ 6.43–7.47 ppm),
a broadened singlet from the CH=N proton (δ 8.17–
8.53 ppm), and a singlet from the NH protons (δ 10.79–
11.45 ppm). Nonequivalent aromatic protons in IVb ap-
peared as doublets with a coupling constant J of 2.3 Hz.
Reduction of the temperature from 130 to 70°C
leads to doubling of the NH, CH=N, and OCH2 proton
signals in the spectrum of IVa due to restricted rotation
about the amide C(O)–NH bond, while further reduc-
tion of the temperature to 30°C induced additional
805

BARSUKOVA et al.
806
Scheme 1.
O
O
O
O
O
O
EtO
O
OEt
H2NNH
O
NHNH2
N2H4 ·H2O
–3EtOH
O
O
O
O
O
OEt
NHNH2
I
II
O
R2
R1
N
O
N
N
R1
N
O
t-Bu
Bu-t
H
H
II
+ 3
–3H2O
O
R3
O
N
R1
N
H
CHO
IIIa, IIIb
IVa, IVb
t-Bu
R1 =
; R2 = OH, R3 = H (a); R2 = H, R3 = OH (b).
R2
R3
Bu-t
splitting of each of the above signals into three com-
ponents (see figure). Analogous signal splitting was
observed by us previously in the spectrum of calix[4]-
arene bishydrazone [8]. Presumably, at a temperature
close to ambient hydrazone IVa in solution is repre-
sented by an equilibrium mixture of four conformers
with cis/cis/cis, cis/cis/trans, cis/trans/trans, and trans/
trans/trans orientations of the hydrazone fragments.
(a)
Harom
OH
Harom
NH
t-Bu
OCH2
CH=N
(b)
(c)
δ, ppm 11
10
9
8
7
6
5
4
1.5
1H NMR spectra of 2,2′,2″-[benzene-1,3,5-triyltris(oxy)]tris[N′-(3,5-di-tert-butyl-4-hydroxybenzylidene)acetohydrazide] (IVa) in
DMSO-d6 recorded at (a) 130, (b) 70, and (c) 30°C.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 6 2014

SYNTHESIS OF ACYLHYDRAZONES OF STERICALLY HINDERED HYDROXY...
807
Scheme 2.
EtO
O
O
OH
Bu-t
t-Bu
Bu-t
t-Bu
I
2
–2AcOH
OH
HO
O
CH2OAc
Bu-t
Bu-t
O
O
O
OEt
VI
OEt
V
Each cis- or trans-hydrazone fragment is sensitive to
the conformation of the two other hydrazone fragments
adopting cis/cis, cis/trans, or trans/trans conformation,
corresponding signal from the two other OCH2C(O)
fragments. Presumably, protons in the first OCH2C(O)
group appear in the area shielded by π-electrons of
aromatic rings in the hydroxybenzyl substituents.
1
which eventually determines the observed H NMR
pattern.
Dibenzyl derivative VI was used to synthesize the
corresponding acylhydrazones as shown in Scheme 3.
Like compounds IVa and IVb, proton signals of acyl-
hydrazones VIIIa and VIIIb were readily assigned in
With a view to obtain new polyphenolic structures
tris-ester I was subjected to benzylation with acetate
V. Presumably, steric factors allow introduction of
only two sterically hindered hydroxybenzyl fragments
into molecule I (Scheme 2). The use of excess benzyl
acetate V and attempts to introduce the third hydroxy-
benzyl fragment into preliminarily isolated compound
VI were unsuccessful. The structure of VI as pentasub-
stituted benzene derivative was confirmed by the pres-
ence of one aromatic proton signal (δ 6.19 ppm) in the
1H NMR spectrum, as well as of double sets of signals
from protons in the OCH2C(O), OCH2CH3, and CH3
groups with an intensity ratio of 2:1. It should be
noted that the signal of the OCH2C(O) group in the
ortho position with respect to the two hydroxybenzyl
substituents appears 0.5 ppm upfield relative to the
1
the H NMR spectra recorded at 130°C. Here, a good
correlation with the spectra of IVa and IVb was ob-
served. In the spectra of VIIIa and VIIIb the chemical
shift of protons in the benzylidenehydrazinocarbonyl-
methoxy fragment in the ortho position with respect to
the two 4-hydroxybenzyl fragments differs from the
chemical shift of analogous protons in the two other
fragments. As noted above for ester VI, the first
OCH2C(O) signal is located in a stronger field.
The isolated compounds containing sterically hin-
dered phenolic and hydrazone fragments attract inter-
est from the practical viewpoint as polyfunctional in-
hibitors of radical chain oxidation processes. On the
Scheme 3.
H
N
H2NNH
O
O
O
O
R1
N
Bu-t
Bu-t
t-Bu
t-Bu
N2H4 ·H2O
3IIIa, IIIb
VI
–3EtOH
–3H2O
OH
OH
HO
O
HO
O
N
Bu-t
Bu-t
Bu-t
O
O
O
Bu-t
O
O
O
N
NHNH2
NHNH2
NH
VIIIa, VIIIb
HN
R1
R1
VII
t-Bu
R1 =
; R2 = OH, R3 = H (a); R2 = H, R3 = OH (b).
R2
R3
Bu-t
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 6 2014

BARSUKOVA et al.
808
other hand, both sterically hindered phenols and acyl-
hydrazones are known as pharmacophores responsible
for various kinds of biological activity [9, 10], which
stimulates interest in further versatile studies of such
hybrid structures.
and 0.06 mL of acetic acid; reaction time 30 h. Yield
0.60 g (82%), white powder, mp 198–200°C. 1H NMR
spectrum (DMSO-d6, 130°C), δ, ppm: 1.30 s (27H,
t-Bu), 1.43 s (27H, t-Bu), 4.75 s (6H, OCH2), 6.43 s
4
(3H, Harom), 7.16 d (3H, Harom, JHH = 2.4 Hz), 7.36 d
(3H, Harom, 4JHH = 2.4 Hz), 8.53 s (3H, CH=N), 11.45 s
(3H, NH), 11.55 br.s (3H, OH). Mass spectrum, m/z:
992 [M + H]+, 1014 [M + Na]+, 1030 [M + K]+. Found,
%: C 69.44; H 8.26; N 14.28. C57H78N6O9. Calculated,
%: C 69.06; H 7.93; N 14.53. M 991.28.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker
Avance-600 spectrometer at 600.13 MHz; the chemical
shifts were measured relative to the residual proton
signals of the deuterated solvents. The mass spectra
(MALDI-TOF) were obtained on a Bruker Ultraflex III
instrument using plastic and metal targets and 2,5-di-
hydroxybenzoic acid as matrix.
Triethyl 2,2′,2″-[2,4-bis(3,5-di-tert-butyl-4-hy-
droxybenzyl)benzene-1,3,5-triyltris(oxy)]triacetate
(VI). A mixture of 2.28 g (5.94 mmol) of ester I,
3.63 g (13.06 mmol) of acetate V, 10 mL of acetic
acid, and 0.02 mL of perchloric acid was stirred for 3 h
at 20°C. The precipitate was filtered off, washed with
water, and dried in air. Yield 3.31 g (68%), white
Tris-ester I was synthesized according to the proce-
dure described in [11].
1
powder, mp 166–167°C (from acetonitrile). H NMR
2,2′,2″-[Benzene-1,3,5-triyltris(oxy)]tris(aceto-
hydrazide) (II). A mixture of 0.80 g (2.08 mmol) of
ester I, 1.3 g of hydrazine hydrate, and 8 mL of DMF
was heated for 2 h under reflux. The mixture was
cooled and poured into water, and the precipitate was
filtered off, washed with water, and dried in air. Yield
0.61 g (86%), white powder, mp >300°C (decomp.).
1H NMR spectrum (DMSO-d6), δ, ppm: 4.43 s (6H,
CH2), 6.20 s (3H, Harom), 9.32 br.s (3H, NH). Mass
spectrum, m/z: 365 [M + Na]+, 381 [M + K]+. Found,
%: C 42.48; H 5.65; N 24.16. C12H18N6O6. Calculated,
%: C 42.10; H 5.26; N 24.56. M 342.31.
3
spectrum (CDCl3), δ, ppm: 1.23 t (3H, CH3, JHH
=
3
7.0 Hz), 1.27 t (6H, CH3, JHH = 7.0 Hz), 1.38 s (36H,
t-Bu), 3.97 s (4H, ArCH2), 4.04 s (2H, OCH2C=O),
4.19 q (2H, OCH2CH3, JHH = 7.0 Hz), 4.26 q (4H,
3
3
OCH2CH3, JHH = 7.0 Hz), 4.54 s (4H, OCH2C=O),
4.96 s (2H, OH), 6.19 s (1H, Harom), 7.10 s (4H, Harom).
Mass spectrum: m/z 821 [M]+. Found, %: C 70.57;
H 8.61. C48H68O11. Calculated, %: C 70.22; H 8.35.
M 821.06.
2,2′,2″-[2,4-Bis(3,5-di-tert-butyl-4-hydroxyben-
zyl)benzene-1,3,5-triyltris(oxy)]tris(acetohydrazide)
(VII). A mixture of 0.66 g (0.80 mmol) of compound
VI, 0.4 g of hydrazine hydrate, 5 mL of DMF, and
1 mL of water was heated for 2 h under reflux. The
precipitate was filtered off, washed with water, and
dried in air. Yield 0.51 g (81%), white powder,
2,2′,2″-[Benzene-1,3,5-triyltris(oxy)]tris[N′-(3,5-
di-tert-butyl-4-hydroxybenzylidene)acetohydrazide]
(IVa). A mixture of 0.2 g (0.58 mmol) of hydrazide II,
0.45 g (1.93 mmol) of aldehyde IIIa, 5 mL of DMF,
5 mL of ethanol, and 0.04 mL of acetic acid was stirred
for 26 h at 80°C. The mixture was cooled, and the
precipitate was filtered off, washed with hot ethanol,
and dried in air. Yield 0.50 g (86%), white powder,
1
mp 285–287°C. H NMR spectrum (DMSO-d6), δ,
ppm: 1.28 s (36H, t-Bu), 3.81 s (2H, OCH2C=O),
3.84 s (4H, ArCH2), 4.27 br.s (6H, NH2), 4.48 s (4H,
OCH2C=O), 6.53 s (1H, Harom), 6.56 s (2H, OH),
6.92 s (4H, Harom), 8.88 s (2H, NH), 9.15 s (1H, NH).
Mass spectrum, m/z: 779 [M + H]+, 801 [M + Na]+,
817 [M + K]+. Found, %: C 65.15; H 7.80; N 10.40.
C42H62N6O8. Calculated, %: C 64.76; H 8.02; N 10.79.
M 778.99.
1
mp 225–227°C. H NMR spectrum (DMSO-d6,
130°C), δ, ppm: 1.44 s (54H, t-Bu), 4.80 br.s (6H,
OCH2), 6.32 s (3H, OH), 6.79 s (3H, Harom), 7.47 s
(6H, Harom), 8.17 br.s (3H, CH=N), 10.79 s (3H, NH).
Mass spectrum, m/z: 992 [M + H]+, 1014 [M + Na]+,
1030 [M + K]+. Found, %: C 69.46; H 8.30, N 14.12.
C57H78N6O9. Calculated, %: C 69.06; H 7.93; N 14.53.
M 991.28.
2,2′,2″-[2,4-Bis(3,5-di-tret-butyl-4-hydroxyben-
zyl)benzene-1,3,5-triyltris(oxy)]tris[N′-(3,5-di-tert-
butyl-4-hydroxybenzylidene)acetohydrazide]
(VIIIa). A mixture of 0.20 g (0.26 mmol) of hydrazide
VII, 0.19 g (0.80 mmol) of 3,5-di-tert-butyl-4-hy-
droxybenzaldehyde (IIIa), 5 mL of DMF, 5 mL of
ethanol, and 0.02 mL of acetic acid was stirred for 20 h
2,2′,2″-[Benzene-1,3,5-triyltris(oxy)]tris[N′-(3,5-
di-tert-butyl-2-hydroxybenzilidene)acetohydrazide]
(IVb) was synthesized in a similar way from 0.25 g
(0.73 mmol) of hydrazide II and 0.56 g (2.41 mmol) of
aldehyde IIIb using 6 mL of DMF, 6 mL of ethanol,
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SYNTHESIS OF ACYLHYDRAZONES OF STERICALLY HINDERED HYDROXY...
809
at 80°C. The mixture was poured into water, and the
precipitate was filtered off and dried in air. Yield
0.32 g (87%), white powder, mp 245–246°C. 1H NMR
spectrum (DMSO-d6, 130°C), δ, ppm: 1.30 s (36H,
t-Bu), 1.42 s and 1.43 s (54H, t-Bu), 4.00 s (4H,
ArCH2), 4.25 br.s (2H, OCH2C=O), 4.81 br.s (4H,
OCH2C=O), 5.94 br.s (2H, OH), 6.70 s (1H, Harom),
6.77 s (3H, OH), 7.03 br.s (4H, Harom), 7.42 s and
7.44 br.s (6H, Harom), 8.05 s (2H, CH=N), 8.15 s (1H,
CH=N), 10.49 br.s (3H, NH). Mass spectrum, m/z:
1429 [M + H]+, 1451 [M + Na]+, 1467 [M + K]+.
Found, %: C 73.34; H 8.84; N 5.49. C87H122N6O11.
Calculated, %: C 73.18; H 8.61; N 5.89. M 1427.96.
Russian Federation (base part of the state contract for
2014–2016).
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2,2′,2″-[2,4-Bis(3,5-di-tert-butyl-4-hydroxyben-
zyl)benzene-1,3,5-triyltris(oxy)]tris[N′-(3,5-di-tert-
butyl-2-hydroxybenzylidene)acetohydrazide]
(VIIIb) was synthesized in a similar way from 0.30 g
(0.39 mmol) of hydrazide VII and 0.30 g (1.27 mmol)
of aldehyde IIIb using 6 mL of DMF and 6 mL of
ethanol; reaction time 24 h. Yield 0.43 g (84%), white
1
powder, mp 165–167°C. H NMR spectrum
(DMSO-d6, 130°C), δ, ppm: 1.31 s (54H, t-Bu), 1.32 s
(9H, t-Bu), 1.43 s (18H, t-Bu), 1.45 s (9H, t-Bu),
4.05 s (4H, ArCH2), 4.12 s (2H, OCH2C=O), 4.76 s
(4H, OCH2C=O), 6.02 s (2H, OH), 6.84 s (1H, Harom),
7. Syakaev, V.V., Podyachev, S.N., Buzykin, B.I., Laty-
pov, Sh.K., Habicher, W.D., and Konovalov, A.I.,
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4
7.00 s (4H, Harom), 7.12 d (1H, Harom, JHH = 2.5 Hz),
4
7.14 d (2H, Harom, JHH = 2.5 Hz), 7.36 d (2H, Harom
,
4JHH = 2.5 Hz), 7.37 d (1H, Harom, JHH = 2.5 Hz),
8.37 s (2H, CH=N), 8.49 s (1H, CH=N), 11.02 s (2H,
NH), 11.06 s (1H, NH), 11.50 br.s (3H, OH). Mass
spectrum, m/z: 1429 [M + H]+, 1451 [M + Na]+, 1467
[M + K]+. Found, %: C 73.53; H 8.84; N 5.52.
C87H122N6O11. Calculated, %: C 73.18; H 8.61; N 5.89.
M 1427.96.
4
10. Kitaev, Yu.P. and Buzykin, B.N., Gidrazony (Hydra-
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This study was performed under financial support
by the Ministry of Education and Science of the
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 6 2014